Standard operating procedure Title: Review of orphan designation at the time of granting/varying a marketing authorisation Status: Public Document no.: SOP/H/3190 Lead author Approver Effective date: 9-FEB-16 Name: Agnieszka Wilk- Name: Kristina Larsson Review date: 9-FEB-19 Signature: ON FILE Supersedes: Kachlicka Signature: ON FILE SOP/H/3190 (22-MAY-2015 TW 3401) Date: 9-FEB-16 Date: 9-FEB-16 TrackWise record no.: 4642 1. Purpose This SOP describes the procedure for reviewing the orphan designation at the time of the initial authorisation of an orphan medicinal product, or an extension of indication (type II variation) for a designated orphan product with a new orphan condition. The procedure runs in parallel with the adoption of the opinion by the CHMP and the granting of or variation to a marketing authorisation by the European Commission. 2. Scope This SOP applies to: Committees Secretariat Service in Scientific Committee Support Department in Procedure Management and Committees Support Division Legal Department Medical and Health Information Service in Communication Department in Stakeholders and Communication Division Orphan Medicines Office in Human Medicines in Product Development Scientific Support Department, Regulatory, Science and Innovation Support Department in Human Medicines Research and Development Support Division Procedure Management Department in Procedure Management and Committees Support Division Regulatory Affairs Office in Regulatory, Science and Innovation Support Department in Human Medicines Research and Development Support Division 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged. 3. Responsibilities It is the responsibility of each Head of Office/Service to ensure that this procedure is adhered to within their office/service. The responsibility for the execution of a particular part of this procedure is identified in the right-hand column of section 9. 4. Changes since last revision Introduction of two deadlines for submission of maintenance report: at time of submission of CHMP application (for accelerated review and type II variation) or at day 121 for regular MA procedure Introduction of pre-assessment TC with sponsor Removal of validation of the sponsor’s maintenance report Introduction of quality check of the review reports by HoO Sending oral explanation invitations to sponsors following CHMP opinion Introduction of negative opinions check by AF-LD and D-RS-REA 5. Documents needed for this SOP Template 1a - Request for report on maintenance of orphan designation at time of MA (located at X:\Templates\Others\OD Post COMP) Template 1b - Request for updated report on maintenance of orphan designation at time of MA (located at X:\Templates\Others\OD Post COMP) Template 2 - Report on maintenance of orphan designation at time of MA - receipt confirmation (located at X:\Templates\Others\OD Post COMP) Template 3a - Review of OD at MA - EMA-COMP report (located at X:\Templates\Others\OD Database\Review of OD at MA - EMA-COMP report) Template 3b - Presentation on review (located at X:\Templates\Others\OD Post COMP) Template 3c – Eudralink message for sending LoQ and invitation to oral hearing (located at X:\Templates\Others\OD Post COMP) Template 4a – COMP coordinator’s comments on review (located at X:\Templates\Others\OD Post COMP) Template 4b – COMP coordinator’s reader’s guidance on review (located at X:\Templates\Others\OD Post COMP) Template 5a - Review of OD at MA – positive opinion (located at X:\Templates\Others\OD Database) Template 5b - Review of OD at MA – negative opinion (located at X:\Templates\Others\OD Database) Template 6a - Review of OD at MA – opinion to EC outcome (located at X:\Templates\Others\OD Post COMP) Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 2/11 Template 6b - Review of OD at MA – opinion to sponsor outcome (located at X:\Templates\Others\OD Post COMP) Template 6c - Template letter informing sponsor on outcome (located at X:\Templates\Others\OD Post COMP\Review of OD at MA – negative opinion to sponsor) Template 6d - Template letter informing sponsor on outcome (located at X:\Templates\Others\OD Post COMP\Review of OD at MA – sponsor notified of final negative opinion to EC) 6. Related documents SOP/H/3004 on tasks of the product team on the handling of the initial marketing authorisation application SOP/H/3046 on preparation of the public summary of opinion for orphan medicinal product designation SOP/H/3049 on orphan medicinal product designation SOP/H/3371 on preparation and publication of the public summary of opinion on the review of orphan designation at the time of marketing authorisation WIN/H/3047 on checking-in of applications for orphan designation Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (2003/C 178/02) http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2003:178:0002:0008:en:PDF Procedural advice http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_00039 2.jsp&mid=WC0b01ac058061f019 Sponsor’s report on the maintenance of the designation criteria at the time of marketing authorisation application for a designated orphan medicinal product (template): http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2015/02 7. Definitions AF-LD Legal Department CHMP application In the context of this SOP, use of the term applies to the initial marketing authorisation application or to a type II variation (extension of indication) application for a new indication covered by an orphan product designation CHMP Committee for Medicinal Products for Human Use COMP Co COMP Co-ordinator COMP Sec COMP Secretariat (in C-CS-SCS) COMP Committee for Orphan Medicinal Products C-PM Procedure Management Department in Procedure Management and Committees Support Division Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 3/11 D-DS-OME Orphan Medicines Office in Product Development Scientific Support Department in Human Medicines Research and Development Support Division DREAM Document records electronic archive management D-RS-REA Regulatory Affairs Office in Regulatory, Science and Innovation Support Department in Human Medicines Research and Development Support Division EC European Commission EudraLink The European medicines regulatory network’s secure file-transfer system used for exchanging information for regulatory purposes LoQ List of questions MA Marketing authorisation MHI writer Medical writer (in S-CO-MHI) MMD Managing meeting documents system OME Asst Assistant (in D-DS-OME) OME Co Co-ordinator (scientific officer in D-DS-OME) OME HoO Head of Orphan Medicines Office (in D-DS-OME) OME line listing Tabular information on MAA application for orphan medicines prepared by DDS-OME updated monthly and tabled in MMD for COMP meetings PM Product manager (in C-PM) S-CO-MHI Medical and Health Information Service, Communication Department in Stakeholders and Communication Division SIAMED Product information and application tracking system Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 4/11 8. Process map/ flow chart Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 5/11 9. Procedure Declarations of interest are checked and evaluated for all staff before involvement according to SOP/EMA/0101 and SOP/EMA/0040 listed under “Related documents”. All messages containing confidential information must be sent via EudraLink. All procedural timelines and application guidance are published on the EMA website. Unless no longer available, COMP Co and OME Co remain the same as per orphan designation procedure. CHMP procedural timelines mentioned below apply to the assessment of an initial MA application. In the case of extension of indications (type II variations), the timelines should be adapted to the ongoing CHMP procedure. It is the responsibility of the OME Co to know where the product is in the procedure and what the most recent discussions in the CHMP contain. Step Action Responsibility Presubmission phase of CHMP application 1 Inform D-DS-OME of upcoming CHMP application (initial MA or PM extension of indication) for an orphan indication (for initial MA applications, see SOP/H/3004) and invite D-DS-OME representative to a pre-submission meeting if needed. 2 If no longer available, coordinate appointment of EMA Co. OME Asst 3 Attend pre-submission meeting and highlight to the sponsor OME Co procedure for review of orphan designation and requirement to submit a maintenance of orpan designation report. Major anticipated maintenance issues may be flagged during the meeting. After submission of CHMP application 4 Inform D-DS-OME of completed validation of the CHMP application. PM 5 If not received, request the sponsor to submit the maintenance OME Asst report to D-DS-OME (at time of submission the CHMP application for accelerated review or at day 121 of regular MA procedure) (Template 1a). 6 On submission of the maintenance report, acknowledge receipt OME Asst (Template 2) informing about a possibility to hold a preassessment TC. Download the sponsor’s maintenance report in DREAM. Save in DREAM the review report (Template 3a) and the presentation (Template 3b) templates and complete administrative data. Forward relevant DREAM links to the OME Co. Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 6/11 Step Action Responsibility 7 Organise a monthly internal review of orphan designations meeting OME Asst inviting OME Cos 8 Examine the maintenance report, and notify the sponsor in writing OME Co of any major issues identified. 9 If requested by the sponsor, organise a pre-assesment TC to OME Asst discuss these issues. 10 Chair the orphan designation review pre-assessment TC with OME Co the sponsor. When major issues are anticipated/identified, request from the sponsor missing data. 11 Advice on the next steps of the review procedure. Run SIAMED report on orphan products with on-going MA COMP Sec procedures. Cross check status of procedures with the CHMP meeting documents (agenda, draft summary of outcomes and annexes). Update relevant COMP agenda listing including new CHMP applications for orphan medicinal products. Table the listing in MMD for forthcoming COMP meeting for nomination of COMP coordinators. Assessment / adoption of COMP opinion on review of orphan designation 12 Attend monthly review of orphan designations meeting and OME Co discuss ongoing CHMP applications; if necessary, identify experts or patient’s representatives and inform the COMP secretariat accordingly. Around day 150 for initial MA application and around day 90 of accelerated procedure, draft the report on review of orphan designation (Template 3a). If major issues remain unaddressed request additional data from sponsor ahead of the COMP discussion and request from the sponsor the updated report (Template 1b). 13 Send the review report to COMP Co for comments. This should OME Co be done well before COMP pre-mailing corresponding to the COMP meeting taking place prior to the CHMP meeting where the product is scheduled for opinion, attach Template 4a. Attend the summary report meeting to internally discuss the draft review report. 14 Download COMP Co comments in DREAM and link in the review Standard operating procedure SOP/H/3190, Public EMA/71584/2007 OME Asst Page 7/11 Step Action Responsibility report. Link the review report and presentation in the COMP meeting folder. 15 OME Co Discuss the report and product with the COMP Cos via telephone or email. 16 Update the review report if necessary. Prepare slides for the COMP plenary. Insert product expected for adoption of an opinion at next COMP Sec CHMP meeting in COMP agenda for first discussion at the COMP meeting. Table in MMD review report from a shortcut to documents and presentations folder where meeting documents are linked for COMP meeting and mailings. Table relevant CHMP assessment report. 17 Co-ordinate first discussion in the COMP meeting. OME Co 18 If COMP trend is negative, go to step 19. OME Co If COMP trend is positive, go to step 35. 19 Co-ordinate adoption of LoQ by COMP. OME Co 20 After the COMP meeting finalise the review report with the list OME Co of questions for sending to the sponsor. Make sure any text copied from the CHMP assessment report has been deleted. 21 Perform quality check of the review reports with LoQ. OME HoO 22 Format and send the review report with LoQ (DREAM version label OME Asst “with list of questions”) to sponsor informing about deadline for written response (two weeks before next COMP meeting) (Template 3c). 23 Include product with CHMP positive opinion adopted at last CHMP COMP Sec meeting for a second COMP discussion and/or an oral explanation in COMP agenda for the next meeting (product with CHMP negative opinion should also be included in COMP agenda for information only). 24 Receive responses to LOQ and link in review reports (DREAM OME Asst version label “with response to LoQ”). 25 Forward responses to COMP Co with request for comments, attach OME Asst Template 4b. Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 8/11 Step Action Responsibility 26 After discussion by CHMP on CHMP application: OME Co If CHMP outcome is negative, go to step 27. If CHMP outcome is positive and a positive opinion is adopted, go to step 30. 27 If CHMP adopts a negative opinion, go to step 28. If the applicant withdraws the MA application before the CHMP OME Co adopts a negative opinion, there is no further need to review the orphan designation and the procedure ends here. 28 If the applicant asks for a review of the CHMP negative opinion, OME Co put the OME second discussion by COMP on hold and go to step 29. If the applicant does not request a review of the CHMP negative opinion, there is no further need to review the orphan designation and the procedure ends here. 29 If the outcome of the CHMP review is positive and a positive OME Co opinion is adopted, go to step 30. If the outcome of the CHMP review is negative and a negative opinion is adopted, there is no further need to review the orphan designation and the procedure ends here. 30 Send to sponsor invititation to oral explanation to be held at the OME Asst COMP meeting following adoption of CHMP positive opinion (Template 3c). 31 Update slides for the plenary discussion. OME Co 32 Coordinate oral explanation and second discussion in the COMP OME Co meeting. 33 34 If COMP trend is negative, go to step 34. If COMP trend is positive, go to step 35. Inform sponsor of negative trend, and of regulatory options OME Co OME Co and consequences (including appeal procedure, delay of marketing authorisation decision by the EC). If sponsor does not request a withdrawal of orphan designation from EU Register, go to step 35. If sponsor requests a withdrawal of orphan designation from EU Register, inform PM and finalise the review report (version label “final”), go to step 47. 35 Ensure adoption of grounds for review opinion. OME Co 36 Inform PM of COMP opinion. OME Co Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 9/11 Step Action Responsibility 37 Go to SOP/H/3049 and follow steps in opinion phase. OME Co/OME Asst Return to this SOP and go to step 38. If COMP opinion is positive, go to step 39. If COMP opinion is negative, go to step 40. Format review report and save (with DREAM version label 38 39 OME Co OME Asst “adopted”). Send COMP positive opinion (Template 5a) to EC (Template 6a). Send COMP positive opinion and review report to sponsor (Template 6b), go to step 47. 40 Forward review report with the grounds for negative opinion to AF- OME HoO LD and D-RS-REA for the check. 41 Send COMP negative opinion (Template 5b) and review report to OME Asst sponsor with information on possibility to appeal within 90 days of receipt of opinion (Template 6c). Appeal 42 43 Receive response from sponsor. If sponsor appeals, go to step 43. If sponsor does not appeal, go to step 46. Go to SOP/H/3049 and follow steps in appeal phase. Return to this SOP and go to step 44. OME Co/OME Asst OME Co/OME Asst 44 Inform PM of COMP opinion. OME Co 45 Revise review report with outcome of appeal (version label OME Co “adopted post-appeal”). 46 Send final opinion to EC (Template 6a) and to sponsor (Template OME Asst 6b in case of appeal (from step 45) or Template 6d in case of no appeal (from step 42)). Public summary of opinion 47 Refer to SOP/H/3371 for preparation of the public summary of MHI writer/OME Co opinion on the review of orphan designation at the time of granting/varying a marketing authorisation. 48 Upon notification of EPAR publication send “Recommendation OME Asst for maintenance of orphan designation” to webteam for publication. Update product information sheet with details of the marketing authorisation and trasmit to webteam for update for the Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 10/11 Step Action Responsibility relevant orphan webpage. (see SOP/H/3046). 10. Records Records produced from this procedure are stored in accordance with WIN/H/3047. Standard operating procedure SOP/H/3190, Public EMA/71584/2007 Page 11/11